1. Field of the Invention
The invention relates to a laboratory scale continuous flow hydrogenation process of given samples under normal, i.e. not supercritical conditions. In particular, the invention relates to a laboratory scale continuous flow hydrogenation process exploiting a laboratory scale continuous flow hydrogenation apparatus comprising a reservoir, a feed pump, a collecting element with two inlets and an outlet, a hydrogenation reactor and a pressure-adjusting unit, all connected into a flow path, as well as a hydrogen source and a valve transmitting a gas stream only into a single direction and connected between the hydrogen source and the second inlet of the collecting element, wherein the pressure-adjusting unit is connected into the flow path after the hydrogenation reactor.
2. Description of the Related Art
Hydrogenating processes (from now on, hydrogenation) are widely used methods of modern chemical industry (including also pharmaceutical industry). Hydrogenation is used in the chemical synthesis of organic compounds: hydrogen is incorporated into starting molecules—optionally in the presence of a catalyst—at given positions and thereby qualitatively different molecules are generated from the starting molecules.
In pharmaceutical industry, to develop a new active ingredient molecule a great number of new molecules is synthesized from the starting molecules, wherein the new molecules can even be used later on as the starting molecules of a subsequent synthesis. A common feature of the processes applied is that generally only a tiny amount (i.e. at most a few milligrams) of material is produced in a single synthesis, however, the number of new substances obtained in syntheses performed consecutively increases rapidly. Consequently, the effective handling of the numerous compounds being generated in the syntheses requires the highest possible amount of automatization in the process.
This problem especially strongly arises in the field of combinatorial chemical syntheses, where a relatively fast and automated synthesis/derivatisation, as well as analysis of molecules of a whole library is needed.
U.S. Pat. No. 6,156,933 and International Publication No. WO 03/099743 both disclose a laboratory scale continuous flow hydrogenation apparatus and a hydrogenating process exploiting such an apparatus. The apparatuses concerned comprise a reservoir that stores the substance to be hydrogenated or its solution (from now on, the sample solution), a feed pump in communication with the reservoir, a mixer connected to the feed pump by one of its inlets, a hydrogen source connected to a further inlet of the mixer through a compressor, a hydrogenation reactor connected to the outlet of the mixer, a heating/cooling means and a pressure reduction unit connected to the outlet of the reactor. A catalyst is arranged within the reactor for effecting the hydrogenation reaction. The pressure reduction unit comprises a valve and has at least two outlets. The valve's task is to control the flow rate measured in the reactor, and thereby the pressure prevailing within the flow path of the apparatus.
By using said apparatuses and within the processes making use of the apparatuses concerned one performs a so-called supercritical hydrogenation. The main point of supercritical hydrogenation is that a carrier medium (a so-called fluid, being inert as far as hydrogenation is concerned) is used for effecting hydrogenation which, due to its specific pressure and temperature, is capable of carrying a huge amount of dissolved hydrogen. The advantage of supercritical hydrogenation over hydrogenation performed under non-supercritical circumstances is that hydrogen, which poorly dissolves in non-supercritical organic solvents, is almost completely miscible with supercritical fluids, and hence, by making use of such fluids, a great deal of hydrogen can be delivered to the actual location of the reaction.
Accordingly, the apparatuses used for carrying out hydrogenation reactions under supercritical conditions also comprise a unit for assuring the feed of the fluid needed by the supercritical hydrogenation; this unit is connected to a third inlet of the mixer via its outlet. While hydrogenation is taking place in the apparatuses, the sample solution, the fluid and the hydrogen necessary for hydrogenation are all fed into the mixer, and the mixture being formed within the mixer is then passed into the reactor. In the meantime, the mixture is made supercritical (that is, its pressure and temperature values are set to fall into the vicinity of the fluid's critical point or to induce supercriticality thereof), as a consequence of which hydrogen completely blends with the fluid getting supercritical. The hydrogenation takes place within the reactor—in the supercritical state—and the mixture leaving the reactor and containing the product then flows into the pressure reduction unit, wherein by decreasing the pressure, the product is separated from the fluid and is withdrawn for further utilization through one of the outlets. The fluid and the hydrogen that had not been consumed in the reaction are simply let off to the surroundings or circulated back to their sources for recycling purposes.
Furthermore, U.S. Pat. No. 5,725,756 discloses a continuous laboratory scale hydrogenation process to be carried out strictly under supercritical conditions. Said U.S. patent also discloses a laboratory scale continuous flow experimental setup with a reactor for effecting the process. As shown in FIG. 1 of the document at issue, a feed stock also containing the sample to be hydrogenated is supplied by means of a HPLC pump into the flow path of the setup from a reservoir storing the feed stock as a mixture of a solvent and the sample. Supercritical conditions required for the reactions are provided within the reactor, wherein the catalyst arranged in the reactor is previously subjected to a careful pre-treatment process.
International Publication No. WO 2004/014542 describes a method and a device for conducting batch-type, i.e. non-continuous laboratory scale chemical experiments involving first and second reactants, wherein the first reactant is provided as a liquid mixture of a solvent and a sample material in a reaction vessel, and the second reactant is formed in particular by a catalyst that is preferably pre-treated under certain conditions before being introduced into the reaction vessel for achieving the reaction of the first reactant.
International Publication No. WO 00/09647 discloses a batch-type or a continuous laboratory scale hydrogenation process that is conducted under supercritical conditions. The sample material to be hydrogenated is mixed with a solvent, particularly with ethanol, and stored in and supplied as a stock feed directly from a reservoir by means of a metering pump.
A common disadvantage of the above discussed apparatuses and processes operating essentially under supercritical conditions is that hydrogenation performed under supercritical conditions requires the usage of structural elements handling the fluid (eg. feeding thereof, inducing a change in its pressure and temperature and accomplishing its separation). The application of these structural elements increases the dimensions and the operational risk of the apparatuses, makes the construction and the operation of the apparatuses, as well as the effectuation of the hydrogenating processes more complicated and significantly raises the production costs. A further disadvantage of said apparatuses and processes is that depending on the starting materials used for the in-situ production, i.e. within the reactor, of hydrogen needed to perform the hydrogenation, besides the final product, undesired and reactive by-product(s) also build(s) up in certain cases. Furthermore, the application of the apparatuses concerned is also disadvantageous when the final derivatisation operations of combinatorial chemistry are performed, as in this case the library synthesis is required to take place as rapidly as possible with the least possible extent of human interference. In certain cases this can also result in a need for a fast and automated replacement of the inert fluid and the catalyst used, for which the laboratory scale continuous flow apparatuses disclosed in the above cited documents are not conditioned at all.